Many bioactive agents including pharmaceuticals, nutrients, vitamins and so forth have a “functional window”. That is to say that there is a range of concentrations over which these agents can be observed to provide some biological effect. Where the concentration in the appropriate part of the body (e.g. locally or as demonstrated by serum concentration) falls below a certain level, no beneficial effect can be attributed to the agent. Similarly, there is generally an upper concentration level above which no further benefit is derived by increasing the concentration. In some cases increasing the concentration above a particular level results in undesirable or even dangerous effects.
Some bioactive agents have a long biological half-life and/or a wide functional window and thus may be administered occasionally, maintaining a functional biological concentration over a substantial period of time (e.g. 6 hours to several days). In other cases the rate of clearance is high and/or the functional window is narrow and thus to maintain a biological concentration within this window regular (or even continuous) doses of a small amount are required. This can be particularly difficult where non-oral routes of administration (e.g. parenteral administration) are desirable. Furthermore, in some circumstances, such as in the fitting of implants (e.g. joint replacements or oral implants) the area of desired action may not remain accessible for repeated administration. In such cases a single administration must provide active agent at a therapeutic level over the whole period during which activity is needed.
Various methods have been used and proposed for the sustained release of biologically active agents. Such methods include slow-release, orally administered compositions, such as coated tablets, formulations designed for gradual absorption, such as transdermal patches, and slow-release implants such as “sticks” or miniature syringe-type devices implanted under the skin.
One method by which the gradual release of a bioactive agent has been proposed is a so-called “depot” injection. In this method, a bioactive agent is formulated with carriers providing a gradual release of active agent over a period of a number of hours or days. These are often based upon a degrading matrix which gradually disperses in the body to release the active agent.
The most common of the established methods of depot injection relies upon a polymeric depot system. This is typically a biodegradable polymer such poly(lactic acid) (PLA) and/or poly(lactic-co-glycolic acid) (PLGA) and may be in the form of a solution in an organic solvent, a pre-polymer mixed with an initiator, encapsulated polymer particles or polymer microspheres. The polymer or polymer particles entrap the active agent and are gradually degraded releasing the agent by slow diffusion and/or as the matrix is absorbed. Examples of such systems include those described in U.S. Pat. No. 4,938,763, U.S. Pat. No. 5,480,656 and U.S. Pat. No. 6,113,943 and can result in delivery of active agents over a period of up to several months. These systems do, however, have a number of limitations including the complexity of manufacturing and difficulty in sterilising (especially the microspheres). The local irritation caused by the lactic and/or glycolic acid which is released at the injection site is also a noticeable drawback. There is also often quite a complex procedure to prepare the injection dose from the powder precursor, and this procedure must be conducted at the point of care just prior to administration.
From a drug delivery point of view, polymer depot compositions also have the disadvantage of accepting only relatively low drug loads and having a “burst/lag” release profile. The nature of the polymeric matrix, especially when applied as a solution or pre-polymer, causes an initial burst of drug release when the composition is first administered. This is followed by a period of low release, while the degradation of the matrix begins, followed finally by an increase in the release rate to the desired sustained profile. This burst/lag release profile can cause the in vivo concentration of active agent to burst above the functional window immediately following administration, and then drop back through the bottom of the functional window during the lag period before reaching a sustained functional concentration. Evidently, from a functional and toxicological point of view this burst/lag release profile is undesirable and could be dangerous. It may also limit the equilibrium concentration which can be provided due to the danger of adverse effects at the “peak” point.
A highly effective non-polymeric depot system was disclosed in WO2005/117830, in which a combination of a diacyl lipid or tocopherol, a phospholipid, and an oxygen containing organic solvent are combined to provide a controlled-release matrix. Such a system has considerable advantages, including a transition from low-viscosity to high-viscosity upon exposure to an aqueous environment, and the facility to provide a gradual release of active agent over a long period from a biocompatible and biodegradable composition. The disclosure of this document is hereby incorporated herein by reference.
Lipid-based systems such as that discussed above can also be used for other purposes by suitable choice of components, including the lipids, solvents and other additives used and their proportions. Such systems have advantages in being able to solubilise and deliver certain active agents which are otherwise difficult to dissolve for standard administration methods (e.g. WO2005/046642). Furthermore, the compositions can be selected to be bioadhesive, which allows delivery of active agents to a body surface over a sustained period (e.g. WO2006/075123).
The components of the delivery systems indicated above are highly biotolerable. Indeed, many of these are endogenous lipids, and can be beneficial even in the absence of an active pharmaceutical ingredient (API). This is particularly the case for bioadhesive formulations such as those indicated above, where the skin or mucosal surface may be soothed and/or protected by the composition itself, aside from any action by any API.
One limitation of previously known lipid controlled-release formulations is that many active agents and even the lipid components themselves can be susceptible to oxidative degradation. Various antioxidant compounds are known to offer some protection against this oxidative degradation but few of these are compatible with lipid based systems. It would therefore be of considerable advantage to provide an antioxidant/lipid combination which was compatible and provided protection of an active agent (such as an API) and/or of at least one lipid component against oxidative degradation.
The present inventors have now surprisingly established that thiol-containing antioxidants are unusually well suited to lipid formulations, and thus allow for such formulations to be stored for longer periods and/or have longer duration of action than other types of antioxidants previously tested.